Effects Of Celecoxib On Voltage-gated Calcium Channel Currents In Rat Pheochromocytoma Cells

BACKGROUNDCyclooxygenase-2(COX-2)plays crucial roles in the occurrence and progression of tumors.However,to date,the mechanisms of specific COX-2 inhibitor on the prevention of cancer remain unclear. Interestingly,the anti-tumor effect by specific COX-2 inhibitors has been reported via both COX-2-dependent and COX-2-independent mechanisms.PURPOSERecent studies have demonstrated the potential use of COX-2 inhibitors as a chemopreventive anti-tumor agent.Inhibition of COX-2 signaling pathway decreased the activity of protein kinase A, which plays an important role in regulating voltage gated calcium channels.In our present study,we characterized a novel mechanism by which celecoxib block the calcium currents via L-type calcium channels in a COX-2-independent manner.Our data highlighted the COX-2-independent therapeutic potential of celecoxib for the treatment of cancer.METHODS Whole-cell patch clamp technique was used to observe concentration-dependent effects of celecoxib on I_Ba,effects of celecoxib on electrophysiological properties of VGCC,effects of rofecoxib and NS-398 on I_Ba,effects of nifedipine,omega-conotoxin GVIA,omega-agatoxin IVA and SNX-482 on celecoxib's inhibition of I_Ba.RESULTSApplication of celecoxib at 0.01,0.1,1,10,and 100μM increasingly inhibited I_Ba.The effect of celecoxib on I_Bais concentration dependent. Celecoxib significantly up-shifted theⅠ-Ⅴcurve to the more positive level.Treatment the cells with rofecoxib or NS-398 failed to inhibit the VGCC currents,which suggested that celecoxib might block VGCC currents via a COX-2-independent signaling pathway.When PC12 cells were treated with L-type calcium channel blocker, nifedipine,the cells became insensitive to celecoxib.After pretreatment of the cells with N-type,P/Q type or R-type calcium channel blocker,celecoxib inhibited to IBa different extents,which implied that the L-type VGCC was the main target of celecoxib inhibition.And celecoxib exerted its inhibitory effect via stabilizing the inactivated state.CONCLUSIONSCelecoxib inhibited VGCC current in PC12 cells via L-type calcium channels,which is dose dependent and COX-2 independent.